This invention relates to novel compounds, pharmaceutical compositions and a method of inhibiting the 5-lipoxygenase pathway of arachidonic acid metabolism in an animal in need thereof which comprises administering to such animal an effective, 5-lipoxygenase pathway inhibiting amount of a diaryl-substituted imidazole fused to a thiazole, pyrrolidine, thiazine or piperidine ring or a pharmaceutically acceptable salt thereof.
Ciba-Geigy AG., U.K. Patent Application GB 2,039,882, published Aug. 20, 1980, discloses compounds of the formula ##STR1## wherein the 1,3-diazacyclopent-2-ene ring may have a further double bond, Alk represents lower alkylene that separates the sulfur atom from the nitrogen atom by 2 to 4 carbon atoms, Ar.sub.1 and Ar.sub.2 represent, independently of one another, an optionally substituted phenyl, pyridyl or thienyl radical and n is 0, 1 or 2, provided that at least one of the radicals Ar.sub.1 and Ar.sub.2 is not phenyl when Alk represents ethylene and the 1,3-diazacyclopent-2-ene ring represents an imidazole ring, and the salts thereof. Compound 1 is not specifically disclosed. The Ciba-Geigy reference alleges that such compounds exhibit anti-inflammatory and antiexudation effects in the rat kaolin paw-oedema test or in the rat turpentine pleuritis test; that the unsaturated compounds in particular exhibit an excellent effect in the adjuvant arthritis test; and that such compounds also have an analgesic effect as shown in the phenyl-p-benzoquinone test in mice; inhibit prostaglandin synthetase in vitro; protect against fatal pulmonary embolism in rabbits (i.e., are anti-thrombotic); and that the tetrahydro compounds exhibit a strong effect in the pertussis oedema test. The rat kaolin paw oedema test and the rat turpentine pleuritis test are useful in detecting compounds which are cyclooxygenase inhibitors but are of no known utility in detecting or suggesting compounds which are inhibitors of the 5-lipoxygenase pathway. The adjuvant arthritis test is useful for detecting compounds which are inhibitors of prostanoid synthesis, but is of no utility for disclosing or suggesting compounds which are inhibitors of the 5-lipoxygenase pathway. The phenyl-p-benzoquinone test is useful for detecting compounds which are cyclooxygenase inhibitors, but is of no known utility in detecting or suggesting compounds which are inhibitors of the 5-lipoxygenase pathway. The observation that compounds of the Ciba-Geigy reference inhibit prostaglandin synthetase in vitro (cyclooxygenase) is of no utility in detecting or suggesting compounds which are inhibitors of the 5-lipoxygenase pathway. The observation that the compounds of the Ciba-Geigy reference are anti-thrombotic in rabbits is of no known utility in detecting or suggesting compounds which are inhibitors of the 5-lipoxygenase pathway. The pertussis oedema test is useful in detecting compounds which are cyclooxygenase inhibitors, but is of no known utility in detecting or suggesting compounds which are inhibitors of the 5-lipoxygenase pathway.
Bender et al., U.S. Pat. No. 4,175,127, issued Nov. 20, 1979 disclose compounds of the formula ##STR2## in which R.sub.1 and R.sub.2 are the same or different, but one of which always being pyridyl, are pyridyl or phenyl optionally monosubstituted by a lower alkoxy, lower alkyl, lower alkylthio, chloro, fluoro, bromo, or trifluoromethyl or a pharmaceutically acceptable acid addition salt or oxide derivative thereof. Bender et al. also discloses that such compounds have utility as antiarthritic agents. Such antiarthritic activity is disclosed as the result of test results from adjuvant-induced polyarthritis in rats. Although not claimed, the Bender patent also suggests, at column 3, lines 66-68, that compounds of Formula A also have antiinflammatory or immunoregulatory properties in addition to their antiarthritic activity. The Bender patent states, at column 4, lines 47-50, that such anti-inflammatory activity is produced by some of the Formula A compounds in the carrageenan-induced rat paw edema test. The Bender patent also states, at column 4, lines 51-65, that species of the Formula A compounds have the ability to regulate cell-mediated immunity as shown in procedures such as the oxazolone-induced contact sensitivity test procedure in which mouse paw volume is measured.
Lantos et al., J. Med. Chem., 27, 72-75 (1984), also disclose that certain 5,6-diaryl-2,3-dihydroimidazo [2,1-b]thiazoles have antiinflammatory activity in the carrageenan-induced rat paw edema and adjuvant arthritis assay in rats. Both the adjuvant-induced polyarthritis assay in rats and the carrageenan-induced rat paw edema test are useful in detecting compounds which are inhibitors of prostanoid synthesis, mediated by the prostanoids formed by the enzyme cyclooxygenase, but are of no known utility in detecting or suggesting compounds which are inhibitors of the generation of 5-lipoxygenase products (such as HETES, LTB.sub.4 and peptidoleukotrienes). The oxazolone-induced contact sensitivity test in which mouse paw volume is measured is useful in detecting compounds which are immunostimulatory, but is of no known utility in detecting or suggesting compounds which are inhibitors of the 5-lipoxygenase pathway.
Lantos et al., U.S. Ser. No. 737,137, filed May 29, 1985, disclose an improved method for the preparation of compounds of the formula: ##STR3## in which R is H, halo, C.sub.1-2 -alkyl, C.sub.1-2 -alkoxy or trifluoromethyl. Lantos et al. state that such compounds have antiarthritic activity. There is no further statement in this reference as to how such antiarthritic activity was determined. Such a blanket statement of anti-arthritic utility does not disclose to one of skill in the art that such compounds have 5-lipoxygenase pathway inhibiting activity. Lantos et al. also disclose compounds of the formula: ##STR4## in which: R is H, halo, C.sub.1-2 alkyl, C.sub.1-2 alkoxy or trifluoromethyl;
R.sup.2 is H or ##STR5## R is C.sub.1-8 alkyl, C.sub.1-8 alkoxy, phenyl, phenoxy, benzyl or benzyloxy. PA1 n is 0, 1 or 2; PA1 R.sub.1 can be H; PA1 R.sub.2 can be H; PA1 A is CH.sub.2 or CH.sub.2 CH.sub.3 ; PA1 R.sub.3 and R.sub.4 are independently selected from phenyl substituted with lower alkyl, lower alkylamino, lower alkoxy or halogen; PA1 R.sub.5 and R.sub.6 are each H or join to form a double bond at the 2,3-position. PA1 n is 0, 1 or 2; PA1 A is CH.sub.2 or CH.sub.2 CH.sub.2 ; PA1 B and C are independently selected from H, methyl, ethyl or dimethyl; PA1 One of R.sup.a or R.sup.b must be selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, monosubstituted phenyl wherein said substituent is selected from C.sub.1-3 dialkylamino, C.sub.1-3 alkylamino, N-(azacyclo C.sub.5-6 alkyl), cyano, 2,2,2-trihaloethoxy, N-C.sub.1-3 alkanamido, N-(C.sub.1-3 alkyl)-(C.sub.1-3 alkanamido) or prop-2-ene-1-oxy; or disubstituted phenyl wherein said substituents are independently selected from C.sub.1-4 alkyl or C.sub.1-3 alkoxy or the disubstituents together form a methylenedioxy group; and the other of R.sup.a or R.sup.b is selected from: PA1 provided that: PA1 n is 0, 1 or 2; PA1 A is CH.sub.2 or CH.sub.2 CH.sub.2 ; PA1 B and C are independently selected from H, methyl, ethyl or dimethyl; PA1 One of R.sup.c or R.sup.d must be selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, monosubstituted phenyl wherein said substituent is selected from C.sub.1-3 dialkylamino, C.sub.1-3 alkylamino, N-(azacyclo C.sub.5-6 alkyl), cyano, 2,2,2-trihaloethoxy, N-C.sub.1-3 alkanamido, N-(C.sub.1-3 alkyl)-(C.sub.1-3 alkanamido) or prop-2-ene-1-oxy; or disubstituted phenyl wherein said substituents are independently selected from C.sub.1-4 alkyl or C.sub.1-3 alkoxy or the disubstituents together form a methylenedioxy group; and the other of R.sup.c or R.sup.d is selected from: PA1 provided that: PA1 n is 0, 1 or 2; PA1 A is CH.sub.2 or CH.sub.2 CH.sub.2 ; PA1 B and C are independently selected from H, methyl, ethyl or dimethyl; PA1 R.sup.1 and R are independently selected from PA1 A is CH.sub.2 or CH.sub.2 CH.sub.2 ; PA1 B and C are independently selected from H, methyl, ethyl or dimethyl; and PA1 R.sup.6 is selected from: PA1 provided that when A is CH.sub.2 and B and C are H, R.sup.6 is other than phenyl or monosubstituted phenyl wherein said substituent is halo, C.sub.1-3 alkoxy, C.sub.1-4 alkyl, CF.sub.3 or C.sub.1-3 alkylthio, PA1 A is CH.sub.2 or CH.sub.2 CH.sub.2 ; PA1 B and C are independently selected from H, methyl, ethyl or dimethyl; and PA1 One of R.sup.4 and R.sup.5 must be H and the other is selected from:
Cherkofsky et al., U.S. Pat. No. 4,064,260, issued Dec. 20, 1977 discloses compounds of the formula ##STR6## in which n is 0, 1 or 2, and R and R.sup.1 are independently selected from monosubstituted phenyl wherein said substituent is selected from C.sub.1-4 alkoxy. Cherkofsky et al. also disclose that such compounds have utility as antiinflammatory agents as demonstrated by their activity in the established adjuvant-induced arthritis assay in rats or the phenylquinone writhing test in mice. As stated above, the adjuvant arthritis test is of no utility for disclosing or suggesting compounds which are inhibitors of the 5-lipoxygenase pathway. The phenylquinone writhing test is useful for detecting compounds which are inhibitors of prostanoid synthesis but is of no known utility for disclosing or suggesting compounds which are inhibitors of the 5-lipoxygenase pathway.
Bender et al., U.S. Pat. No. 4,263,311 issued Apr. 21, 1981, discloses compounds of the formula ##STR7## wherein n is 0, 1 or 2, and R.sup.1 and R.sup.2 are independently selected from (a) monosubstituted phenyl wherein said substituent is selected from lower alkoxy, chloro, fluoro, bromo, trifluoromethyl, amino, di-N-N-lower alkylamino or (b) 3,4-methylenedioxyphenyl. Bender et al. also disclose that such compounds have utility (a) in the treatment of arthritis based on their activity in the adjuvant-induced arthritis test in rats and in the carrageenan-induced rat paw edema test; and (b) as immunoregulatory agents based on their activity in the oxazolone-induced contact sensitivity test in which mouse paw volume is measured. As stated above, none of the adjuvant arthritis test, carrageenan edema test or oxazalone sensitivity test have any known utility in detecting or suggesting compounds which are inhibitors of the 5-lipoxygenase pathway.
Bender et al., U.S. Pat. No. 4,186,205, issued Jan. 29, 1980, disclose compounds of the formula ##STR8## wherein R is 4-monosubstituted phenyl and said substituent is selected from C.sub.1-4 alkoxy or chloro, or a non-toxic, pharmaceutically acceptable salt thereof. Bender et al. also disclose that such compounds are useful as (a) antiarthritic agents based on their activity in the adjuvant-induced arthritis assay in rats; and (b) regulators of cell-mediated immunity based on their activity in the oxazolone-induced contact sensitivity test in which mouse paw volume is measured. As stated above, neither the adjuvant arthritis test nor the oxazolone sensitivity test are of any known utility in disclosing or suggesting compounds which are inhibitors of the 5-lipoxygenase pathway.
Bender et al., J. Med. Chem., 28, 1169-1177 (1985), disclose compounds of the formula ##STR9## wherein n is 0, 1 or 2, and R and R.sup.1 are independently selected from (a) monosubstituted phenyl wherein said substituent is selected from C.sub.1-4 alkoxy, halo, 4-amino, 4-acetamido, 4-trifluoromethyl, 4-N(ethyl)-acetamido, 4-ethylamino, and 4-ethyl(methyl)amino; or (b) 3,4-methylenedioxyphenyl. Bender et al. also disclose that some of such compounds are useful as immunoregulatory, anti-inflammatory and antiarthritic agents based on their activity in the adjuvant-induced arthritis test and the mouse subliminal oxazolone-induced contact sensitivity assay. As stated above, the adjuvant arthritis assay is of no utility in detecting or suggesting compounds which are inhibitors of the 5-lipoxygenase pathway. The mouse subliminal oxazolone sensitivity assay is useful in detecting compounds which are immunostimulatory but is of no known utility in detecting compounds which are inhibitors of the 5-lipoxygenase pathway.
Baetz et al., U.S. Pat. No. 4,110,460, issued Aug. 29, 1978, discloses compounds of the formula ##STR10## wherein R and R.sup.1 are independently selected from monosubstituted phenyl wherein said substituent is selected from chloro, bromo, C.sub.1-4 alkoxy, or a pharmaceutically acceptable acid addition salt thereof. Baetz et al. also disclose that such compounds have anti-inflammatory activity based on their activity in the carrageenan-induced edema assay in rats, cotton-induced granuloma assay in rats, ultraviolet induced erythema assay in guinea pigs, and Freund-adjuvant induced arthritis assay in rats. All of such assays are useful for detecting compounds which are inhibitors of prostanoid synthesis, but none of such assays is of any known utility for disclosing or suggesting compounds which are inhibitors of the 5-lipoxygenase pathway. Baetz et al. also disclose that such compounds have utility as antipyretic agents based on their activity in an assay in which hyperthermia was induced in rats by subcutaneous infection with yeast. Such assay is useful for detecting compounds which are cyclooxygenase inhibitors but is of no known utility in detecting or suggesting compounds which are inhibitors of the 5-lipoxygenase pathway. Baetz et al. also disclose that such compounds have analgesic activity based on their activity in the acetic acid writhing test in mice. The acetic acid writhing test is useful for detecting compounds which are cyclooxygenase inhibitors but is of no known utility in detecting compounds which are inhibitors of the 5-lipoxygenase pathway.
Bender et al., U.S. Pat. No. 4,153,706, issued May 8, 1979, disclose compounds of the formula ##STR11## wherein R.sup.1 is 4-substituted phenyl wherein said substituent is selected from lower alkoxy, lower alkylthio, fluoro, chloro, bromo or trifluoromethyl; and R.sup.2 is 4-substituted phenyl wherein said substituent is an election withdrawing group, in particular, fluoro, chloro, bromo or trifluoromethyl. Bender et al. also state that such compounds have antiarthritic activity as measured in the adjuvant-induced polyarthritis assay in rats; and immunoregulatory activity as measured by the oxazolone-induced contact sensitivity test in mice. As stated above, such assays do not disclose or suggest that such compounds have 5-lipoxygenase pathway inhibiting activity.
Davidson et al., U.S. Pat. No. 4,507,481, issued Mar. 26, 1985, disclose compounds of the formula ##STR12## wherein X is O or S(O)n;
Davidson et al. also disclose that such compounds are immunostimulants or immunosuppresants based on (a) their inhibiting or stimulating activity in a chemotaxis assay which measures the ability of a drug substance to influence the movement of murine macrophages responding to complement; (b) their immunosuppressing or activating activity in the Kennedy plaque assay in which an animal's humoral immune system is depressed artificially with 6-mercaptopyrine. Such chemotaxis assay is no known utility for detecting or suggesting compounds which are inhibitors of the 5-lipoxygenase pathway. Such Kennedy plaque assay is of no known utility for detecting or suggesting compounds which are inhibitors of the 5-lipoxygenase pathway. Davidson et al. also disclose that such compounds have antiinflammatory activity as determined by the carrageenan-induced paw edema assay in rats. As stated above, such assay has no known utility in detecting or suggesting compounds which are inhibitors of the 5-lipoxygenase pathway. Davidson et al. also disclose that such compounds have antiviral activity in mice with hepatitis; but such activity is of no known utility in detecting or suggesting compounds which are inhibitors of the 5-lipoxygenase pathway.